We will establish our Center for Causal Modeling and Discovery (CCMD) of Biomedical Knowledge from Big Data as a collaboration among the University of Pittsburgh (Pitt; lead institution), Carnegie Mellon University (CMU), and Yale University (Yale). The CCMD will develop, validate, and disseminate methods, tools, and software based on Causal Bayesian Networks, which will enable the broader scientific community to effectively interrogate large imaging, genomic, and clinical (phenotype) data and derive knowledge on the causality of observed phenomena. We selected three Driving Biomedical Problems (DBPs) on cancer pathways, lung diseases, and brain fMRI as a platform for algorithm and software development. Our overarching goal is to develop and enable the broad usage of, a complete suite of interoperable software' and application programming interface that will help advance BD2K research and education. The activities of the CCMD will be organized in three major components. Data Science Research (DSR), Training and Consortium. The CCMD will be co-led by 3 PIs, each of whom will co-lead an activity component, in consultation with the Center Executive Committee. The Administrative Core (AdminCore) will oversee the overall operation of the CCMD to ensure productive interaction between the teams at the participating institutions, effective integration of the DSR and training activities of the CCMD, efficient development of a computational tools for CMD that will benefit the broader research community, and training of next generation of data scientists equipped with CMD skills necessary to tackle a variety of BD2K problems. The AdminCore will also continually monitor and evaluate the progress made in the three CCMD components, making strategic plans to increase the utility and quality of research, training, and collaborative activities. We will use a detailed logic model and associated metrics as its evaluation framework and will consult with the Center Internal and External Advisory Boards. The AdminCore will be responsible for ensuring access to adequate infrastructure and resources for efficient development and dissemination of CMD tools to benefit the data science and biomedical research communities, in particular the other BD2K Centers.